SE446186B - BETA-LAKTAM SOCIETIES AND PHARMACEUTICAL COMPOSITIONS THEREOF - Google Patents

Description

soovö99-4 (III) where R6 represents a halogen atom; or (C) a group of formula (IV) H 2 -a- where R 7 represents a hydroxy group.

The term "lower alkyl" means a straight or branched alkyl group containing 1-6 carbon atoms. The side chain asterisk and, when R 3 does not represent hydrogen, the cross in the ester group indicate chiral centers which give rise to diastereomeric forms of the compounds of formula I. The invention encompasses all such diastereomers and mixtures thereof.

The salts of the new compounds are salts with pharmaceutically acceptable, non-toxic acids or bases, depending on whether R 2 represents a primary amino group or a carboxy group.

Examples of suitable acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid; Nitric acid, p-Loluenesulphonic acid, motansulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, U, U'-methylenebis (3-hydrexy-? - naphthoic acid) ("Damoic acid") and p- (sulfuric acid) frro- bcnvnid). ' As examples of suitable base salts may be mentioned salts with alkali metals or alkaline earth metal numbers, such as,. _. In sodium, potassium, magnesium or calcium salts, as well as salts with ammonia or suitable non-toxic amines, such as lemalkylminmines, e.g. triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, binsolyl99-4 (2-hydroxyethyl) amine or tris- (2-hydroxyaryl) amine, cycloalkylamines, e.g. dicyclohexylamine, or benzylamines, e.g. N, N '- dibenzylethylenediamine or dibenzylamine. The examples listed above are not limiting of the invention. basic antibiotics are within the scope of the present invention. In some cases it is preferred to use easily soluble salts, while also salts with acid or T 4. that in other cases it may be appropriate to use a salt which is only slightly soluble, e.g. when one_wants to obtain a low fl gv fl rlß effect. A long-lasting effect of a salt mod probcnccid, which inhibits don tubUläPa ULSÖHÜPÉUSPÛ of especially obtained by use / 5 -]: LklnimIY3rurLín; 71r.

In the clinical treatment of bacterial infections, it is a serious problem that β-lactamase-producing bacteria appear with increasing frequency. 'Α-lactamases inactivate most penicillins and cephalosporins, and it is well known that # 9-lactamases produced by both gram-positive and gram-negative bacteria greatly contribute to bacterial resistance to β-α-lactam antibiotics. Several natural β-lactamase inhibitory agents, such as clavulanic acid and clivanic acid, have been described. Recently, a number of semi-synthetic ß-lactam compounds have been shown to exhibit similar biological properties, e.g. penicillanic acid 1,1-dioxide, δ-chloropenicillanic acid 1,1-dioxide, a series of kiavulanic acid derivatives. b-bromopenicillanic acid, methicillin sulfone and quinacillin sulfone. With a few exceptions, these compounds show only a weak antibacterial effect against most gram-positive and gram-negative organisms, but they strongly inhibit a wide range of β-lactamanes.

In combination with selected penicillins and cephalosporins, the said compounds act synergistically against a number of β-lactamase-producing bacteria, as they protect the penicillins and cephalosporins against inactivation.

As mentioned above, the present invention relates to novel compounds which are particularly intended for enteral use and which exhibit a potent antibacterial action in which the beneficial action against β-lactamase-producing bacteria is achieved due to the fact that the compounds in one and the same molecule contains both a portion of an antibacterially highly active penicillin and a portion of a potent β-lactamase inhibitor. However, two conditions are necessary in order to be able to utilize the properties of the new associations. soo1099-4 4 The compounds must be able to be absorbed from the gastrointestinal tract, and during or after the absorptin they must be hydrolyzed while releasing the Vpenicillin and β-lactamase inhibitor. It has been shown that both of these conditions are met, and the new compounds according to the invention are therefore valuable precursors to both penicillin and / / lactamase inhibitors.

Studies with experimental animals and volunteers have shown that the new compounds are easily absorbed from the gastrointestinal tract. During or after the absorber, they are hydrolyzed to release equimolar amounts of the two components, ie. penicillin and the β-lactamase inhibitor, which give rise to simultaneous high levels of the two components in blood and tissues. In this way, the penicillins are prevented from being inactivated by β-lactamases.

The good absorption and hydrolysis in vivo of the compounds of the invention have been demonstrated in experiments with volunteers, which have been orally given one of the new compounds, namely the hydrochloride of 1,1-dioxopenieillanoyloxymethyl-6- (D-A-amine -Ü- phenylacetamido) penieillanate, hereinafter referred to as VD-1827. The same group of subjects were also given equimolar months by the orally active ampicillin precursor pivampicillin and potassium fl-penicillanate-1,1-dioxide, respectively. The results obtained are summarized in Tables L and II below. 8001099-4> uLm pmwcm + Q sw flflfl @ fi cwm ^ ov «Ew@mumHwcmm|.Broc fl àørw: mvumu fi hmme fl xo fi æocw flflfl o fi cmmuxuWUx fl. A mm« ww «| ü> * wo om S 3.0 mmJ 3 .... .... f ... Éïovm _ w ww .Um: w mwó nuó oJ m., wá: é så .fm: J ßån »J 2.9 / Jm ^ + mz 2.0 ßwïo nwó .ßå mi .... .fn 0.4 .á cJ .ÄJHL _ 5A mm mw om mod .Üó wmó f. __...,. beast. mä md nå ÜAÃM 2 mn Om oß w0.0 ßa.O mm.O m. «ß. ~ ß. @ wm ~.« ß.w nO.ov M2 cb hm mb c0.0 mA.O æ: .G uH æ. ~ í ß.v Hu wN oH mw.0%: O 4 m.,. m <m 4 m _ <m .q m <äïø wá J N A md 3.0. ws fl hwnuw fi c fl äøm mmpww mmñs fl s cowmmm ”nmxmmnnm“ wow> m Q, wm fi nwmmmuß flfl mß \ HE må co fl pmhucwocoxüñmwm v:. . .F f \. wz fl cwmHmmpum>> m Enom fl Ammn fl mm ¶.n fl H flfi @ fl ue @> fi m ma mw fl @ «h«> m »0sv. @ flfi @ fl Mohv% @« * ßNw fl- m> ms oß fl .m æhowußw fl mp pmp @ mp pmp @ @sm> fl @ we mm fl. <> m wn fl nmmuw fi c fi ëwm Hmno nwuuw mmcomamm | wxmmnmm m fl smpwmm wo: c flfififi u fl msm> m wc fl møcmwpzc fl nz soø co fl ßmuwcmocoxaenmü- 4- 6 hours after oral administration of A. 73 mg potassium penicillanate 1,1-dioxide (equivalent to 65 mg 7 penicillanic acid 1,1-dioxide) in aqueous solution B. 170 mg VD-1827 hydrochloride (equivalent to 65 mg penicillanic acid-1 , 1-dioxide) in aqueous solution. .. ï "s" i ".fu, '' - i» S Försoksperson Irinut on A '' B nu '2. ä 60 Mk 11.0 i 76 PJ 9.5 77 MM 5.5 63 LA' h. 5 79 Medelvärde- 5_2 _ 71 The results in Table I show that oral administration of VD-1827 gives similar serum levels of ampicillin as obtained after oral administration of an equimolar dose of pivampicillin, and the results in Table I also show that the urinary excretion of ampicillin after administration of VD-182® is comparable to the urine excretion obtained after administration of pivampicillin.

The results in Table II show that only 5.5% of penicillanic acid 1,1-dioxide was excreted in the urine after oral administration of the corresponding potassium salt. In contrast, after administration of an equimolar amount of VD-1827, a 71% urinary excretion of penicillanic acid 1,1-dioxide was obtained, which shows the very good oral absorption of VD-1827.

By using the compounds according to the invention, the antibacterial spectrum of the penicillin in question can be greatly extended, since ß-ectamase-producing strains also become sensitive to the treatment. As mentioned above, such β-lactamase-producing strains have become increasingly common and have given rise to a serious problem in clinical therapy. The compounds according to the invention are therefore extremely valuable. Therapeutically, the new compounds have clear advantages over pure combinations of the penileillins and β-Jaktamas inhibitors to which they are hydrolyzed, or combinations of orally active esters thereof. In many β-lactamase inhibitors, such as picnicillanic acid 1,1-dioxide, e.g. poorly or irregularly from the gastrointestinal tract (see Table II above). Many penicillins, including ampicillin and carbenicillin, are also incompletely absorbed. In addition, individual variations in the rate of absorption of different penicillins and β -lactamasin inhibitors can in many cases lead to a situation where the active components are not present at the same time or are not present in an optimal ratio, even if the two drugs are administered prematurely. . Some readily hydrolyzable esters of penicillins and β-lactamase inhibitors are better absorbed from the gastrointestinal tract than the corresponding free acids. However, hydrolysis of such esters in the organism gives rise to the formation of inactive by-products, and although these by-products are relatively non-toxic, it is not desirable to expose the organism to unnecessary metabolites. Another disadvantage of using combinations of easily hydrolysable esters of the penioillins and β-lactamase inhibitors is that the ester groups increase the molecular weight of the compounds and thus the size of the dosage units. By using the compounds according to the invention, the size of the dosage units can be considerably reduced. In addition, the absorption of such esters usually does not take place simultaneously, even if the compounds are given simultaneously to the patient.

The pivaloyloxymethyl ester of ampicillin is absorbed e.g. very rapidly, while the sparingly soluble pivaloyloxymethyl ester of the β-lactamase inhibitor penicillanic acid 1,1-dioxide is absorbed much more slowly.

All these disadvantages are avoided by using the new compounds according to the invention.

It has been found that the in vitro syncrpl between different: β-lactamase inhibitors and different penicillins is particularly strong when the ratio between the two_components is between 351 ooh 1: 3. Since the different penicillins have slightly different biological half-lives and distribution properties, the ratio between the components released by the new compounds may vary to some extent in organs and tissues, but usually the ratio between the preferred limits given above. 8001099-4 s Below are described various methods for preparing the novel compounds of the invention.

According to one method, one starts from a compound of the formula '«U U E. nftn-co-Nxrç p ¿/..u\p * H! B Ûl: --- N * vx H I ~ O-PH ~ A ill o n, 3 where H1, RB and A have the meanings given above, and B denotes an azido group, on protected amino group, e.g. a benzyloxycarbonylamino group, a triphenylmethylamino group, a 1-methoxycarbonylpropen-2-ylamino group or a 1-N, N-dimethylaminocarbonylpropen-2-ylamino group, or a protected carboxy group e.g. a benzyloxycarbonyl group or a cyanomethoxycarbonyl group, or similar known protected amino or carboxy groups. The compound of formula V is subjected to hydrogenolysis or hydrolysis depending on what the symbols A and E denote.

The reactions are carried out in mixtures consisting of a suitable organic solvent, e.g. ethyl acetate or tetrahydrofuran, and water in a volume ratio of from 3: 1 to 1: 3, preferably 1: 1, and at temperatures from 0 to 5000. If B represents a side group or another group which can be converted into an amino or carboxy group by hydrogenolysis, one can use as catalyst e.g. palladium on carbon, and if B represents a group which is sensitive to hydrolysis, such hydrolysis can be catalyzed by means of an acid, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid or p-trifluorosulfonic acid.

The intermediates of formula V can be prepared by a compound of formula n R -Cn-.co-Nn = S 7 I åš_llf \\ _N,: 1 H (mwwxfä H - () _ (1I- X. Ü I H3 ~ - 9 8001099-4 teaches R1, H5 and B have the above part numbers, own K denotes a leaving group, such as a halogen atom, is reacted with a compound of the formula AM, where A has the meaning given above and M denotes a cation, síízi - »nl Nu +, Kil, a .ännuunïurnj-ux, a Lrl- or * ff-frn-alkylammonium ion, eg a tetrabutylammonium ion.

The reactant fi is passed through a suitable solvent, e.g. dimethylformamide, ethyl nuetate, diuloromethane, anethone or hexamethylphosphoric triamide, for a sufficient time and at a suitable temperature for the desired conversion to take place, usually at a temperature »between 0 and 6000.

According to another method for preparing the intermediates of formula V, in a first step, a compound of formula AM is reacted with a compound of formula VII to form an intermediate of formula VIII Y_cn-x A-TH-X R 3 R 3 (Xr- In the above formulas, R 3 and X have the meanings given above, and Y represents a bromine or iodine atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, a chlorosulfonyloxy group or an M -haloalkoxysulfonyloxy group, wherein Y is a group which is easier to split than group X.

The reaction is carried out in the same manner as described for the preparation of the known compounds of formula VI and is carried out in a suitable solvent, e.g. dimethylformamide, ethyl acetate, dichloromethane, acetone or hexamethylphosphoric triamide, usually at a temperature between 0 and 60 ° C.

In a second step, the intermediate of formula VIII is reacted with a penicillin derivative of the formula _... _...

II R1-CH-CIO-NII: _ | I å "\ _'s - (rx) n: ___ N M. min * 'HI .ll' _n- M i; 8001099-4 10 where R1, B and M have the meanings given above, to form an intermediate If desired, X in the formula V1 can be cleaved, first exchanged into a group which is easier to first step in. According to another embodiment, reacted in a compound of the formula AM with a 6-aminopenicillanic acid ester with formamine-protected derivative thereof, eg with the formula XI, between X or with a trialkyl-silyl derivative, to form a compound H n IEN §; / S \\ / 0 == N -äi ~ - “, _0_rn-X HTI o H3 ( X) (X1) the above symbols have the symbols R3, A and X anically soluble. In the above formulas the reaction is carried out in a suitable organic meaning, at a temperature between 0 and the agent, e.g. dimethylformamide, 30 ° C. Alternatively, intermediates of formula XI may be prepared from either a salt or an amino-protected formula VIII or formula XI or an all by reacting 6-aminopenicillanic acid torn therefrom with a compound of a compound In each step, the compound is reacted with trialkylsilyl derivatives thereof with a reactive derivative of an acid of the formula n -cn_coon_ 1 (x1I) "B and B have the meanings given above. The symbol B may des- The reactive derivative may be rid or an acid bromide; an acid and a carboxylic acid, wherein R 1 except Nn} +, Hail an acid halide, such as an acid hydrochloride; a mixed anhydride with an alkylcolic acid, or a radical obtained T- .GX. VÉIPH an inorganic acid or a sulfonic acid; by reacting the free acid of formula XII with a carbodiimide rllvr N, N'-kurhonyldiïmídnzul or any compound which reacts on RrakLinnen.knn is carried out in an ornnninki solution solution. v an organic solvent and part or in a mixture a guard, at low or slightly elevated temperature. Examples of suitable solvents are dichloromethane, chloroform, ethyl lactate, ace. tonic, dimethylformamide, dimethylacetamide, ether, dioxane and other inert solvents.

The starting materials or intermediates of formulas V, VIII and XI are novel compounds which are also incorporated by the present invention. According to another embodiment, compounds of formula I, wherein R represents a primary amino group, is prepared directly by a one-step process. A salt of an aminopenicillin, e.g. ampicillin or amoxicillin, with the general Eormeln _. -,) - 'z: ._, R PH (' ('Ni HHQ l | Å_3 ______ 7 / \\ i “mg i (un) Ü: ----- \' --- y \\ n in-o The compounds R1, H5, M, A and X have the meanings given above, wherein X preferably represents an iodine atom. The reaction is carried out in a suitable organic solvent, e.g. Ethyl acetate, dichloromethane, chloroform or dimethylformamide, at a temperature between 0 and HOOC, preferably at room temperature In the starting materials of formulas VI, VI, 1X and Xh X are known compounds, or they can be prepared by methods analogous to those used in the preparation. of similar known compounds.

Most of the starting materials of formula A-M and the corresponding acids are known compounds.

The compounds of formula I can be purified and isolated in the usual way, and they can be recovered either as such or in form iv a salt. The compounds can in some cases be obtained as diastureemfra mixtures, which when desired can be dissolved according to known methods, e.g. by chromatography.

The invention also relates to pharmaceutical compositions which can be used in the treatment of infectious diseases in humans and - '.__..___..._..____....._-. 8001099-4 12 animals and which can be administered internally, parenterally or topically.

The compositions of the invention contain as active ingredient at least one compound of Formula I or a salt thereof together with solid or liquid pharmaceutical carriers and / or diluents. > The proportion of therapeutically active component in the pharmaceutical compositions can vary between 1 and 95% by weight. The compositions may be formulated into various pharmaceutical dosage forms, such as tablets, pills, dragees, suppositories, capsules, long-acting tablets, suspensions and the like, containing a compound of formula I or a non-toxic salt thereof in admixture with carriers and / or diluent. Pharmaceutically acceptable, non-toxic, organic or inorganic, solid or liquid carriers and / or diluents may be used to prepare the compositions of the invention. Examples of suitable materials which may be mentioned are gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, polyalkylene glycol, nuffts and other known carriers, adjuvants and / or drug diluents.

The compositions may additionally contain other therapeutically active components, which may conveniently be co-administered with the compounds of the invention in the treatment of infectious diseases, such as other antibacterial agents, antitussives, analgesics, probenecid, etc. It is particularly convenient to use antibacterial agents which act synergistically with one or both of the active components formed in the in vivo hydrolysis of the compounds of the invention. The compounds of formula I may be used either as such or in the form of a salt. The compounds as such are only slightly soluble in water, while many of the salts, e.g. the hydrochlorides and sodium salts, are readily soluble in water.

As stated above, the compounds of the invention may be formulated into pharmaceutical dosage forms, including suspensions and non-aqueous ointments. A pharmaceutical preparation for oral treatment may be in the form of a suspension of one of the compounds of the invention, which preparation contains 10-100 mg of the active compound per ml of vehicle.

Another object of the invention is to select such a dose of the compounds of the invention and such a dosage formulation of the compositions of the invention which can be administered so that the desired effect is achieved without concomitant side effects. in human therapy, the compounds of the invention are conveniently administered to adults in dosage units of the compositions. These dosage units contain from 50 mg up to 2500 mg, preferably from 100 mg to 1000 mg, of the compounds of formula I.

The term "dosage unit" means an undivided dose which can be administered to a patient and is easy to handle and package, which remains in a physically stable state, and which contains either the active material as such or a mixture thereof with solid or liquid , pharmaceutical diluents, carriers, solvents and / or excipients. In the form of dosing units, the new compounds can be administered once or several times a day at suitable intervals, the dosing of course always depending on the patient's condition and taking place in accordance with a doctor's prescription. The daily dose is preferably between 0.25 and 15 g of a compound of formula I or an equivalent amount of a salt thereof, and this daily dose may conveniently be divided into several smaller doses.

In the continuous therapy of patients suffering from infectious diseases, tablets or capsules constitute the appropriate forms of the pharmaceutical preparations, possibly in the form of compositions with a long excretion time.

In veterinary medicine, the above-mentioned pharmaceutical compositions can also be used, preferably in the form of dosage units containing from 50 mg up to 25 g of a compound of formula I or a corresponding amount of a salt thereof.

»For the treatment of breast diseases, especially mastitis in cattle, the antibacterial agent may be administered to the mammary gland in liquid or semi-liquid form, such as an ointment, or administered together with a substantially water-insoluble and oil-insoluble binder in the form of granules.

: Patients suffering from infectious diseases can be treated with the novel compounds of the invention. To adult patients, an effective amount of a compound of formula I is administered, either as such or in the form of a salt, the administration preferably taking place in the form of the dosage units described above. The compounds of formula I are usually administered in amounts of 3-200 mg / kg body weight / day, which corresponds to 0.25-15 g / day for adults, or in equivalent amounts of salts of the compounds of formula I. 8001099 In the treatment of patients, the compounds of the invention may be administered either alone or in conjunction with other therapeutically active compounds, such as probenecid, which help to fight the bacterial infection. Such combined treatment may be carried out with compositions containing several or all of the therapeutically active compounds, or the therapeutically active compounds may be administered in separate compositions, which are administered either simultaneously or at appropriate intervals.

In the treatment of patients, the daily dose can be administered either at a single time or in the form of divided doses, e.g. 2, 3 or H times a day.

The following preparatory examples describe the preparation of new starting materials and intermediates.

Preparative Example 1. C; N-bromopininillanoic acid 1,1-dioxide.

To a stirred solution of 1.90 g (μmol) of potassium purmanganate in 35 ml of water and 1.36 ml (1H mmol) of acetic acid was added dropwise at 0-SCC an ice-cold solution of 1.91 g (6 mmol) of potassium-6N -bromobenicillanate in 25 ml of water. After completion of the addition (ua 15 minutes), the reaction mixture was stirred for a further 20 minutes at the low temperature. The cooling fluid was removed, and to the mixture was added 1.52 g (8 mmol) of solid sodium pyruvic acid to reduce the excess oxidizing agent. The precipitated manganese oxides were filtered off, and to the filtrate (about 60 ml) were added 30 g of solid sodium chloride and 50 ml of ethyl acetate. The pH of the mixture was adjusted to 1.5 by the addition of NN hydrochloric acid with stirring, after which the organic phase was separated. The aqueous phase was re-heated with 25 ml of ethyl acetate, and the combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated in vacuo. The resulting amorphous residue was crystallized from a mixture of ether and diisopropylene 6-hydrobromic acid. -1,1-dioxide with a melting point nv IZH-127 ° c.

A crystalline potassium salt of the above-obtained compound was prepared by adding 5.6 ml of a 1M solution of potassium olyl hexanoate in acetone to a stirred solution of H, 9H r (3 mmol) of 6G-bromopenicillanic acid-1.1 -dioxide in 12 ml of acetone.

NMR Spectrum For Potassium 6-Dihydronymicylanate-1,1-dioxide in CD OD showed signals at ¿= ¿_h3 (5, 3nš 3_5! 3), δ 1.50 (s, 3u; 2433), lance (S, ln; gig) , 5.111 (a, J = 2u7., M; 6 ".I'_I.) 10Ch 5'35 (d: J = 2H2: ln; 5'-I_ [) PPW- '1'CL1",' 1P. : H _ '(, _ \; 1 :: ílnn nylvåjndgg; as internal reference. = M @; ». Aua..a¿ ~ _.._.-...._..._.._. _ , 80Û_1¶Û99-4 15 líïcfl-fggnde exempe__l _____? ¿. 6G -lalnrpcrnicíllfmrfyrn-'I, 'I -díwxlch They worked in the same way as J Preparatory example J but replaced potassium-65 (-bromopeníci fi nnm-Ga / m After crystallization of the product in diinepropyl filters, 6 melting points of 13 M-157 ° C were obtained. The NMR spectrum (CDCl 3) showed signals at δ = 1.50 (S, 3u; 2-cn1), L.6h (S, BH; 2-cgß), H-H6 (ß. LH; 3-H), h_7§ (ds J = \ _ 3Hz, ln; 6_E), and 5.18 (d, J = 1.5Hr, LH; 5 -Q) ppm, Tetramethylsilane was used as internal reference.

A crystalline potassium salt of the above-obtained precursor was prepared by adding an equimolar amount of a 0.8 H solution of potassium 2-ethylhexanoate in acetone to a stirred solution of δ-chloropenicillanic acid 1,1-dioxide in acetone.

Preparative Example 5. Chloromethylpinnyl cilanate-1,1-dioxide.

To a solution of 1.17 g (5 mmol) of penicillanic acid 1,1-dioxide in 7.5 ml of dimethylformamide was added PÄ98 ml (7 mmol) of triethylamine and 2.18 ml (50 mmol) of chloroiodomethane, after which the resulting mixture was stirred at room temperature for N hours. After dilution with 30 ml of ethyl acetate, the mixture was washed with water (3 x 10 ml) and then with a saturated aqueous solution of sodium chloride (R ml), then dried and evaporated in vacuo. The desired compound was obtained as a yellowish oil, which crystallized from a mixture of ether and petroleum ether. The resulting product had a melting point of QH-9600.

The NHR spectrum (CDCl3) showed signals at 00r = 1.U7 (S, 3H; 2-C53), 1.66 (ß, 3n; 2-C53), 3.53 (4, J = 3nz, zu; 6a- 5 and 6p-Q), h.u6 (S, 1u; 3-5), h.6s (c, J = 3n ;, 1n; 5-3), O fi h 5-35 (^ BkV: J = 6U2 » 2U; OCH 2 Cl) Ppm. The tetramethylsllane was used as the internal refrain.

Förbnredande_3§gmQelw fl¿ 1-kloretvlpnníuíllnnat-I, 1 ~ dínxjd.

Work was carried out in the same manner as in Example 3, but the chloro-iodomethane was replaced by the J-chloro-1-iodoethane, and the concentration was increased to 16 hours. There was obtained the J-clerutylpyrinillinyl, 1-dinxide as a yellow oil, which could be purified by dry column chromatography on silica gel (eluting with a mixture of ethyl rotate or polyethylene ether in a volume ratio of 7: 5). 8001099-4 16 Preparative Example 5. Clermethyl-hd -bv flmpeninlllnnnt-1,1-dloxin._ Work was carried out in the same manner as in Preparative Example 5 but the penicillinylurea ~ 1,1 ~ was replaced with the GK -hrompenicillanic acid-1,1 - dioxide. There was obtained chloromethyl-GM-brmpenicillan-1,1-dioxide as a yellowish oil.

The NMR spectrum (CDCIB) showed signals at δ = 1.H8 (S, 3n; 2-cgj), 1.6h (S, 3n; 2-cn3), h.h6 (S, 1n; 3-Q), h .71 (u, J = 1.5 nz, ln; 6-n), 5.17 (u, _J = 1.5 nz, ln; 5_¿), and SQSO (ABkv, J = 6 Hz, EH; OCQZCJ) ynnn. TMS used: as inve reference. _ Éörberednnde exvmpgl_§. Klormvty] -6 / ß ~ brompeniefllanat. one worked in the same manner as in Preparative Example 5 but replaced the penicillanic acid 1,1-dioxide and the triethylamine with potassium 6β-bromopenicillanate. This gave chloromethyl-β-bromopenicillate as a viscous oil.

Preparative Example 7. Clone methyl clavulanate.

Work was carried out in the same manner as in Preparative Example 5, but substituted penicillin-1,1-dioxide and trintylmine min uutrium-clavulanate. Chloromethyl clavulanate was thus obtained.

Preparative Example 8. Kldrmethylpyl nicilanate-1,1-dine oxide. To a suspension of 1.08 g of potassium penicillanate-1,1-dioxide in 12 ml of dimethylformamide was added 1.6 g of bin-methylmethylnulfane, and the resulting mixture was stirred at room temperature for H5 minutes.

After dilution with 50 ml of ethyl ecotate, the mixture was washed with water and then with an aqueous solution of sodium bicarbonate, after which it was dried and evaporated in vacuo. Hänvíd crhülls an oil, which was purified by chromatography on herringbone. The compound thus obtained was identical to the compound described in Preparative Example 3.

Preparative vxvmpul 9. Climethyl-Hm -klnrpvniníllnnnL-1,1-aloxide.

Work was carried out in the same way as in the previous nxcmp fl l K but the penicillanic acid 1,1-dioxide was replaced with the nd-chloropenjví] 1nnnyrn-1,1-dioxide. This gave chloro-methyl-Gd -c] carbonylcinnint-1,1-dioxide as a viscous oil.

The NMR spectrum (CDCl 3) showed signals at δ = 1.H8 (S, 3n; 2-033), 1.6h (S, 3n; 2-C33), u.h7 (S, Ju; s-Q). n.6s (Q, J = 1.5 Hz, uu; 6-5), 5.17 (n, J = 1.5 nu, mn; ä-1). 8001099-4 17,000 -5-31 (ABkv, J = 6 Hz, EU; Üc fl acl) PPM-TMS was used as internal reference. - Preparative Example 10. Iodomethylpenicilanate-1,1-dioxide.

To a solution of 5.6 g (20 mmol) of chloromethylpenicilanate-1,1-dioxide in H5 ml of acetone was added 9% sodium jedide, after which the resulting mixture was stirred at room temperature for 16 hours.

1.15 g of precipitated sodium chloride were filtered off. The solvent was then removed in vacuo, and the resulting residue was treated with a mixture of equal volumes of ethyl acetate and ether. He filtered 6 g of insoluble, sodium iodide, nen filtrate. evaporated under reduced pressure. 7 The residual oil was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and n-hexane in the volume ratio H: 6. After crystallization of the product in ether, the title compound was obtained as colorless crystals with a melting point of 110-120 ° C. Preparatory Example 11. Qβ -aminopenicillanic acid 1,1-dioxide hydrate. A '(A) β-Benzyloxycarbonylaminopycnicilanoic acid 1,1-dioxide.

To a stirred solution of 63.5 g of 6β-benuyloxycarbonylaminopenicillanic acid and 18.1 g of potassium bicarbonate in 1125 ml of water was slowly added (over a period of about US minutes) to 000 a solution of 38 g of potassium permanganate in 915 ml of water. During the oxidation, a pH of 6.5 was maintained in the reaction mixture by adding dilute sulfuric acid. Insoluble material was removed by filtration, and the filtrate was extracted with ethyl ether. The resulting aqueous phase was filtered again, and after adding 600 ml of ethyl acetate, it was acidified to pH 2.5 with stirring. The organic layer was separated, and the aqueous phase was extracted with additional ethyl acetate (2 x 300 mL). After drying, the combined ethyl acetate extracts were evaporated in vacuo. The residue was recrystallized from a mixture of 250 ml of ethyl acetate and 500 ml of petroleum ether.

This gave the pure compound with a melting point of 153-IGHOC. [α] D = _ + 1u6.9 ° (un, 96% 02115011).

(B) Qβ -aminopenicillanic acid 1,1-dioxide hydrate.

A filtered solution of 15.3 g of methylloxycinhonylminnopicillanic acid 1,1-dioxide and H g of potassium hydrogen carbonate in 160 ml of water hydrogenated over 5 g of 10% Pd / BaSO 2 for N hours at a slightly elevated pressure. After filtration and extraction with 100 ml of ethyl ether, the pH of the ice-cold aqueous solution was set at 2.5. The precipitate thus formed was filtered, washed with water and dried in air. After recrystallization from a mixture of dimethylformamide and water, the pure monohydrate was obtained, melting at 199 DEG-200 DEG C. with decomposition. L -1: + 252.9 ° (c = 1, dimethylfermamide).

Preparative Example 12. Chloromethyl-1,1-dioxopenicillanate.

To a mixture of 2.7 g (10 mmol) of potassium ~ 1,1-dioxepenicillanate, 6.0 g (60 mmol) of potassium bicarbonate and 0.3H g (1 mmol) of tetrabutylammonium hydrogen sulphate in 10 ml of water and 15 ml dichloromethane was added to 1.5 ml of chloromethylchlorophelate. After stirring the reaction mixture for 1 hour at 3000, the mixture was filtered, and the organic layer was separated and dried over sodium sulfate. After dilution with 20 ml of 2-propanol, the solution was concentrated to a volume of about 10 ml in vacuo, after which the concentrate was allowed to stand at 500 for 1 hour. The crystals thus formed were filtered off, washed with cold 2-propanol and dried in vacuo. The title compound was obtained as colorless crystals with a melting point of 9D-96 ° C. Preparatory Example 13. 1-Chloroethyl] -1,1-dioxopenicillanate.

To a mixture of U0.7 g (0.15 ml) of potassium 1,1-dioxenpeneilanate, 25.5 g (0.15 mol) of silver nitrate and 7.5 ß of silver oxide in 750 ml of acetonitrile was added H2 ml of 1- chlorine ~ 1-iodide. After stirring the reaction mixture for H8 hours at room temperature, the silver salts were filtered off and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 200 ml of ethyl acetate, and the resulting solution was washed with a saturated aqueous solution of sodium chloride, filtered, dried and evaporated in vacuo. The residue thus obtained was chromatographed on silica gel, eluting with a mixture of hexane and ethyl acetate in a volume ratio of 5: 2. There was thus obtained the title compound as a crystalline mixture of the two diastereomers having a melting point of 130 DEG-132 DEG C. Preparative Example 1N. 1-iodoethyl-1,1-dioxopenicillanai.

To a solution of 30 g (about 0.1 ml) of 1-chloroethyl 1,1-dioxepenicillanate in 100 ml of acetone was added 30 g (0.1 ml) of sodium iodide, after which the resulting reaction mixture was stirred at room temperature. for three days. An aqueous solution of sodium thiosullyate was then added, and the acetone was removed in vacuo. The resulting oil was dissolved in ethyl acetate, and the resulting solution was washed with water, dried and evaporated in vacuo. The residual oil was chromatographed on silica gel, eluting with a 3: 1 mixture of hexane and ethyl acetate. This gave a crystalline mixture (m.p. JBH-13606) of the diastereomers 1-iodoethyl and 1-chloroethyl esters. By microanalytic determination of iodine it was shown that this mixture contained UO% of the iodine compound.

- Preparative Example 15. Chloromethyl-6/5-chromopenicillan.

To a stirred solution of 0.96 g (3 mmol) of potassium Ü¿8-bromopenzicillanate and 1.80 g (18 mmol) of potassium bicarbonate in 9 nl of water and 9 ml of S fi ylac flfl êß S fi ßi fi ß 0.10 E (0, 3 mmol) tetrabusylammonium hydrogen sulfate and Üäfêftef Û, U5 ml (U, 5 mmol) chloromethylchlorosulfonate. The resulting mixture was stirred at room temperature below 1.5 Limmap. The organic phase was separated, and the aqueous phase extracted again with 9 ml of ethyl acetate. The combined organic extracts were washed with Water (2 x 5 ml), dried and concentrated to a volume of about 5 ml under reduced pressure. The concentrate was subjected to dry column chromatography on silica, eluting with a 9: 1 mixture of petroleum ether and ethyl acetate. This gave pure chloromethyl-6; -bromoponylcillant as an almost colorless oil.

NMR'§D0kÜPUN ° ï (CDCl3) showed ninnulcr vin! cf = IÄSH (S, 3n; à-C53), 1.70 (S, 3n; 2-nga), h.5u (S, ln; 3-5), 5.35 and 5.59 (za, J = hnz, zu; 5 -3 «wh 613), wnw 5_77 (Agge, J = 5H2, 3"; OCH2Cl) PPHH Tetramethylsilane was used as internal reference.

Preparative Example 16. Iodomethyl-Gß-bromopenicillanate.

To a solution of 0.82 g (2.5 mmol) of chloromethyl-os-bromopenicillanate in 5 ml of acetone was added 0.75 g (5.0 mmol) of solid sodium iodide.

The resulting mixture was protected from light and stirred at room temperature for 2 hours. The precipitated sodium chloride was filtered off and washed with acetone (2 x 1 ml) and the filtrate was evaporated in vacuo to an oily residue, which was dissolved in 20 ml of ethyl acetate. The resulting solution was washed with water (2 x 10 ml), concentrated over magnesium sulphate and concentrated to a volume of 1 ml under reduced pressure. The concentrate was subjected to column chromatography on silica gel, eluting with a mixture of patrolumeter and ethyl acetate in a volume ratio of 9: 1. He combined the fractions which, in thin layer chromatography, used to contain pure title compound. These fractions were evaporated in a vacuum, with iodine | 1 | o1, yl ~ bß ~ hrnn | 1_ ~ c ~ zi.ic: illmini vrhiilli:: n- "n-oni vn: = v: | r_l.; -_ ui: ilc1_ip , oil.

NMR spectra showed signals at δ = λ =, δ; 3n; 2-cgj), 1.69 (S, 3n; 2-cgs), δ 50 (S, in; 3-5), 5.3h and '8001099-4 20 5.37 (Wi, .T == 1! U2, -2H; 5 ~ I_ {mvh 0-11), "'41 5-97 (Åïdfv: JTÜUÅ, z 2U: ÖUlL» ï) Pznu. fl btrnnmtyïsílan is used nâsnm ínrv P flfi fv fl ns. k Förburßdandc example 17% Chloromethyl-I, 1-dioxo-Gfï - (?, f ~ 1ímot- uxibonsumídu) pnnivillnnat. 1.8 ml (18 mmnl) chlorine per minute 20 min. to a mixture of 6, ¿F (15 mmol) t, 1-dioxo-Oß- (2,6-dimotoxibinamide) pnivillin (m @ ticil1in sulfone), 8.7 (8i mmo1) 'potassium hydrogencrhnnnt by means of U, H1 g (1.5 mmol) tetrabutylammnnïumvälnnnlfut i.1H ml vnttvn_nvh 1H ml dïkl fl vmßtan.

After stirring for a short time, the organic phase is removed, which is then dried and evaporated in vacuo.

The resulting oil crystallized in 90% strength, yielding colorless crystals, melting at 11 DEG-1 DEG C. with decomposition. After two crystallizations in a mixture of acetone and water, an analytical sample was obtained, which melted at 15 DEG-15500 to decompose. 'fïtïâo: + l95O (c = 1, CHCIÉ).

Preparative cXumpn1 18. Judmctyl 1,1-dinx fl-I¶ß- (f, h-d2myto-oxybenzamido) penicillanate. 3 g (20 mmol) of sodium iodide satin in a solution of nv?, .L 4 (5 mmol) of chloromethyl-1,1-dioxo-β- (2,6-dimotoxybinnamide) ponicillanate in 10 ml of acctone, whereupon the resulting mixture qmrördcu overnight at room temperature. Gnnnm tíïlsättnínn av vaifnn uf- fälltes titclförnnin fi cn i form av kríßtnllor, vilke avïíltr fl radcs och tbrkådes Å vakuum. These crystals melted at 153 DEG C. during decomposition.

The product was dissolved in a mixture of acetone containing 96% v / v, after which the acetone was left in vacuo to give the desired crystallisation. Through the establishment of this procedure, the melting point of the product is increased to 169-17OOC (sndcrdb] nin $) - ÄÜXJÉU: + ï9ïÛ (@ = 1, cnclj).

Fövbcrcdnndn example 19. Klnrmøtyl-1,1-dinxn-hd - ¥ lnrn fi ni- cillannt.

He worked in the same way nom in Fövbcrn fl nndn vx fl mpwl 15 but replaced potassium-Gß -brompcnícïllanní fi ï mvd Vn1ium-1,1-dïfxu- 6d_-chloropcnícillanate. After quenching of pvuduki in a mixture of ctcv and diisopropylntur, the colorless crystals, as well as colorless crystals with a melting point of 111 DEG-111 DEG C., were obtained (c = 0.5, CHCl3).

Förbcvudnndv nxpmpvl PH. Jwdmvtyl ~ l, l-di ~ xo ~ h fl -Vl ~ rrunivil- lnnat._ 21: 80ll1099-4 They worked on the same site as in preparatory example 16 but replaced chloromethyl-óß ~ brompenicí1lanatrt with chloromctyl-J,] - djoxo- _6d.-k1orpenicillanate. ' This gave the Little Association as a colorless foam.

The NMR spectrum (CDCl 3) showed signals at δ '= 1.H9 (s, 3n; 2-03 1.62 (S, 3n; 2433), mm (s, m; B-fl). 11-65 3), ° ° h 5.16 (za,.; = 1, .5 Hz, an; 5-5- oohó-n), and 6.oL (An1-: v, .1 = 5 nz, 2H; Oc fl zï) ppm. Tetramethylsilane was used as internal reference.

Preparative Example 21. Chloromethyl-1,1-dioxo-βq-bromopenicilanate.

Work proceeded in the same manner as in Preparative Example 15 but replaced potassium 6,5-bromopenicillanate with potassium f1,1-dioxe-6N-bromopenieillanate. After quenching the product in a mixture of ether and diisopropyl ether, the title compound was obtained as colorless crystals, m.p. 92-9300. fdjšo: + 185 ° (c = 0.5, cHc13) _ t, Preparative example 22. Iodomethyl-1,1-dioxo-6 <Å-bromopunicylanate. Work was carried out in the same manner as in Preparative Example 16, but the chloromethyl-6β-bromopenicillanate was replaced with chloromethyl-1-1-dioxo-6% bromopenicillanate. The title compound was thus obtained as a colorless foam, which could not be crystallized. The NMR spectrum (CDCl 3) revealed signals at δ = 1.U9 (-, 3: 1; z-cg 1.63 (s, 311; z-cgj), 14.141 (s, m; 3-3), 1 ».7o 3) '_ och 5.16 (za, J = 1.5 ny., An; 5-3 Oßh Gn). Ch 6.01 (An = <H - .r = 5 Hz, 2n; OCnqI) ppm, Tetramethylsilane was used as internal reference.

: L Preparatory Example 23. Chloromethyl-6f3-iodopenicillanate.

Work was carried out in the same manner as in Preparative Example 1S, but the potassium β-bromopenicillanate was replaced by the potassium ßβ-iodopenicillanate. Thereby, the title compound was obtained as a weakly zero oil.

The NMR spectrum (CDCl 3) showed signals at dr = 1.5? (s, gnjz-cg 1.71 (s, 3n; 24:33), 14.55 (s. ln; 3-11), 5.1 «o _ 3). own 5.63 (zu, J = 3.5 ng, gl; 5-fl fv¶1 6_n), Uvh 5.78 (Ankv, J = 5.5 H7. 2H; OCQOCI) ppm. Tetramethylsilane was used as internal reference.

Preparatory example'2N. Iodomethyl-6/3-iodopenicillanaf.

Mnn worked on mom just nnm 1 Preparatory Example 16 but replaced the chloromethyl-6/5-bromopenicillanate with chloromethyl-L / 5-iodopenicillanate. The title compound was thus obtained as a yellow lactic oil. ß -8001099- (4 22 NHR spectrum (CDCl 3) showed signals at Cf = 1.53 (S- BHš 2-033), 1.70 (s, JH: 2-053), male (s, m; sg), 5.39 O fl h 5.61 (2a, J = 3.5 m., An; ygw-h 6-1), mh 6.00 (Arn-rv, J = 5.5 Hz, 2H; OC fl nl) ppm, Tetramethylsilarx was used as an internal refractorx.

Preparative Example 25. Klotlnety G- Gß -chloropeniciflananaf fl Worked in the same manner as in Preparative Example 15 but replaced the potassium-öß-well-pycnicillanate with potassium-GÅ -klf-rpr-nieillanate. The title compound was obtained as a colorless O1.131.

NMR spectrum (CDCl 3) showed signals at cf = 1.53 (s. An; 2-0113). 1.69 (s. An; 2-ßI_r,), mal »(s, m, ø-u). 5.21. and 5.62 (zd, -1-1; Hz, 2II; 5-I_I_ and 6-51), nnh 5.80 (Aßkvfhj Hz, 2H; OCQ2Cl) ppm. Tetramethylsilane was used as internal reference.

Preparative Example 26. Tendmethyl-Gß-chloropenicillarxn The procedure was as in Example 16 but replaced the chloromethyl-ßß-bronlperxicillaxxate with chloromethyl-β-chloropenicillanate. The 'pitel compound' was thus obtained as a weak 'yellow-colored oil. The NMH spectrum (CDCl 3) showed signals at d '= 1.52 (s, _nn; Lega), 1.69 (s, 3: 1; z-cnß), h.52 (s, in; 3-31). 5.22 0Ch5.58 (2d-, J_ = ü Hz, 2ll; 5-11 cwnG- fl), 'Wh 5-99 (^ Ül-I \ i, J = 5 ÜZ: 2H; Oc fi àl) ppm,' l- ptramethylsilax was used as an internal reference.

Preparative Example 27. Chloromotyl-Gß-bromopenicil1arxate.

(A) Chloromethyl-β-dibromopenicillanate.

P-Tanlar betacie, in the same manner as in the preliminary example, replaced the potassium-6β-bromopenicillanate with potassium-6,6: dibromopenicillanate. The title compound was thus obtained as a slightly yellowed oil, which crystallized in a mixture of ether and diisopropyl-ether. The product had a melting point of 105-110 ° C (dJD I * 3UUo (c = 0.5, CHCl 3). The IJMR spectrum. (CDCIB) exhibited sir_rl-alm 'at * U = 1. "- U (s, jan; z-cnj), 1-.66 (s, 311; 2 _ <: | _x1) °,: msn (s, now '' j- fl), 5.8o (Ankv ,, r = 5 m., an; c »cz_ | ._, c1), and 5.83 (s. 1H; 3-3) npf fl- Ten-arnezyi- si- lan was used as an 'internal reference.

I (B) Chloroethyl-Gß -hrnrnper1ir: .ílflanni. To a stirred solution of 1.63 g (11 mmol) of bromopenicillanate in H0 ml of dry benzene was added 1.16 g (11 mmol) of tri-23-solo-99-4 n-butyltin hydride under a nitrogen atmosphere at 0 ° C. After stirring at room temperature for 18 hours, the evaporation mixture is evaporated in vacuo. The residual oil was purified by dry column chromatography on silica gel, eluting with a mixture of petroleum ether and ethyl acetate in a volume ratio of 85: 1f. There was obtained Ient_chloromethyl-ββ-dnympenicillanate as a pale yellowish oil.

The NHR spectrum of the product was identical to the point given for the compound prepared in Preparative Example 15.

Preparative Example 28. Bromomethyl 1,1-dioxopenicillanate.

To a solution of 100 g of sodium bromide in 10 ml of N, N-dimethylforamide was added 0.28 g (1 mmol) of chloromethyl-1,1-dioxopicillanate.

The resulting mixture is stirred at room temperature for 20 hours. After dilution with 50 ml of ethyl acetate, the mixture was washed with water (H x 10 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give the desired compound as a yellowish oil.

The NMR spectrum (CDCIB) showed signals at CT: 1.H9 (s, 311; 2-c '| _ 1), 1.6I | (s, 311; 24:53), 3. ~ 3: z (m, an; 6-3, 14A? (s, m; js-Ll), h.75 (m, m; 541), (Sf -J, 5.98 (, \ nkv, .1 = h.5nl¿, 2H;, OC fl2 Br) ppm. TMS was used as internal reference.

The invention is illustrated by the following non-limiting examples. ».

Example 1. 1,1-Dioxopenicillanoyloxymethyl-6- (D-Ä-emino-Q-phenylacetamido) penicillanate hydrochloride. I (A) 1,1-dioxopenicillanoyloxymethyl- 6- (D-N-azido-N-phenyl-acetamido) penicillanate.

To a solution of 2.5 H g (6 mmol) of chloromethyl 6- (DW.-azido-d-phenylacetamido) penicillanate in 35 ml of dimethylformamide was added 1.65 g (6 mmol) of potassium penicillanate-1,1-dioxide, the resulting mixture was stirred at room temperature for 20 hours. After dilution with 10 ml of ethyl acetate, the mixture was washed with water (M x 35 ml) and then with a saturated aqueous solution of sodium chloride (20 ml), then dried and evaporated in vacuo. The yellow oily residue thus obtained was purified by dry column chromatography on silica gel, eluting with a mixture of equal volumes of cyclohexane and ethyl acetate. There was thus obtained the desired compound as a yellowish oil.

The NMR spectrum (CDCl 3) showed signals vidcf = 1.ü3 8001099-4 24 (5, 3n; 2-cgj), 1.52 (S, gu; 2-cgj), 1.59 (S, EF; 2-C33), 1.66 (S, 3n} 2-cgj), 3; hs (s, J = 3nz, an; 6a-g «mn1 6ß-g), 'h.hu (S, in; 3-Q), h.51 ( S, ln; 3-g), h.63 (c, J = 3uz, in; 5-g), 5.13 (S, ln, CQN3), 5.65 (m, an; 5-g and 6-Q), 5.92 (S, zn; ocg2o), 0ch 7.hs (s, 5Hi arom. CQ) ppm.

(DB) i ", β-dioxopeniylanoyloxymethyl- 6- (D-d-amin-Or-phenylacetamido) penicillanate hydrochloride.

A solution of 1.77 g (2.85 mmol) of 1,1-dioxopenicylanoyloxymethyl-β- (D-Ol-azido-d-phenylacetamido) penicillanate in 25 ml of ethyl acetate was introduced into a three-necked flask, which was equipped with a gas inflow and outflow tube, a glass-calomel combination electrode and a burette controlled by an automatic titrator, 20 ml of water and 1.77 g of a catalyst consisting of 10% palladium on carbon were added, The system was then purged with nitrogen, then a stream of hydrogen gas was bubbled through the suspension with stirring, and a pH of 2.5 was maintained in the aqueous phase by adding 0.5 N aqueous hydrogen chloride solution via the automatic titrator. When the acid consumption ceased, the flask was purged with nitrogen until all hydrogen was removed, and the catalyst was filtered off, the aqueous phase was separated and lyophilized to give the desired compound as a colorless foam. The NMR spectrum (D 2 O) showed signals S, sn; 2-cgß), 1. h6 (5, 3n; 2-cgß), 1.58 (S, gu; 2-cgß), 3.56 (m, w; ö fl-fl <> <= h ßß-u). h-GO (sun a-a). Inez (s, 111; 3-31), 5.03 (m, in; 5-Q), 5.27 (s, ln; og-Nn2), 5.53 (S, an; 5-5 and 6-g), 5.97 ( bs, _1u; ocgzo), and 7.53 (5, sn; srpm. eg) ppm, Tetramethylsilane was used as an external reference. §§G¶ggl_§. 1,1-dioxopenicillanoyloxymethyl-6 - ([DW-amino-M - (p-hydroxyphenyl) acetamide] penicillanate hydrochloride. Q _ (A) k 1,1-dioxopenicillandyloxymethyl-6-N- (benzyloxycarbonyl) D '' lös m1 fl0 'd ~ (p-hydroxyphenyl) acetamido] penicillanate.' # 111 a solution of ïluïs 5 (5 mmol) chloromethylpenicillanate-1,1-dioxide (or an equivalent amount of the corresponding iodomethyl ester, which gives a much shorter reaction time) in ml of dimethylformamide was added 2.45 U (5 mmol of potassium 6 - [N- (benzyloxycarbonyl) -D-O- -amino-β- (p-hydroxyphenyl] acetamide] penicillanate, whereupon the resulting mixture of tetramethylsilane was used as internal reference. The mixture was stirred at room temperature for 18 hours After diluting with 100 ml of ethyl acetate, the mixture was washed with water (H x 25 ml), then dried and evaporated in vacuo The residual oil was purified by dry column chromatography on silica gel, eluting with with a mixture of ethyl acetate and petroleum ether in a volume ratio of 8: 2. such as a yellowish oil. (B) 1,1-dioxopenicillanoyloxymethyl-10- [D- * X-amino- ° (- (p-hydroxyphenyl) acetamido] penicillanate hydrochloride.

The benzyloxycarbonyl protecting group of the compound prepared in Example 2 (A) was removed by hydrogenation at atmospheric pressure in the same manner as described in Example 1 (B). The title compound was thus obtained as a colorless; amorphous product. . Example 3 1- (1,1-dioxopenicylanoyloxy) ethyl 6- (D- [6-amino-N-phenylacetamido) penicillanate hydrochloride.

The procedure was the same as in Example x1 (A) but using N-chloroethyl-δ- (D-K-azido-d-phenylacetamido) penicillanate instead of the corresponding chloromethyl ester. This gave 1- (fl-dioxopenicillanoyloxy) ethyl 6- (D- (g-azido-N -phenylacetamido) penicillanate.

By working in the same manner as in Example 1 (B) but replacing the 1,1-dioxopenicillanoyloxymethyl-δ- (D-β-azido-N -phenylacetamide) penicillanate with 1- (1,1-dioxopenicillanoanoyloxy) ethyl 6- ( D-IX-azido-DK - phenylacetamido) penicillanate Prepared 1- (L1-dioxopenicillanoyloxy) ethyl 6- (DW -amino-Q -phenylacetamido) penicillanate hydrochloride as an amorphous product.

Example 14. 1,1-Dioxopenicillanoyloxymethyl-G- (D, L-O (-carboxy-OK-phenylacetamido) penicillanate sodium salt.

(A) 1,1-dioxopenicillanoyloxymethyl-6- (D, L-O 1 -benzyloxycarbonyl-β'-phenylacetamido) penicillanate. IK By working in the same manner as described in Example 2 (A) but replacing the potassium ö-fi-benzyloxycarbonyl-D-1X-amino-W- (p-hydroxyphenyl acet-acetamido] penicillanate with sodium 6- (D, LW-benzyloxycarbonyl) -M - phenylacetamido) penicillanate was prepared the above compound.

(B) 1,1-dioxopenicillanoyloxymethyl-β- (D, L-N-carboxy-d-phenyl-acetamido) penicillanate sodium salt.

To a solution of 1.15 g (2 mmol) of 1,1-dioxopenicylanoyloxymethyl-β- (D, L-UE-benzyloxycarbonyl-OS -phenylacetamido) penicillanate in 20 ml of ethanol was added a catalyst consisting of 10% palladium on carbon . The reaction mixture was hydrogenated at atmospheric pressure until hydrogen gas consumption ceased. The catalyst was then removed by filtration and washed with ethanol, and the filtrate was evaporated in vacuo. The oily residue thus obtained was dissolved in 15 ml of ethyl acetate, after which 15 ml of water were added. The apparent pH of the aqueous phase was adjusted to 7.0 by adding a 0.2N aqueous solution of sodium hydroxide with stirring. The aqueous phase was separated and lyophilized to give the desired compound as a yellowish foam.

Example 5.- Clavulanoyloxymethyl-β- (D- ° (-amino- (X-phenylacetamido) penicillanate hydrochloride. "Worked in the same manner as in Example 1 (A) but replaced the potassium penicillanate-1-dioxide with sodium clavulanate. There was thus obtained clavulanoyloxymethyl- (GD-O1 -azido-Os-phenylacetamide-penicillanate as an angular oil. B By catalytic hydrogenation of the obtained intermediate in the same manner as described in Example 1 (B), the title compound was obtained as an amorphous powder. 1,1-Dioxo-6-O-chloropenicillanoyloxymethyl-O- (D-OK-amino- (X -phenylacetamido) penicillanate hydrochloride.

The procedure was the same as in Example 2 (A), but replacing chloromethylpenicillanate-1,1-dioxide with chloromethyl-olX-chloropenicillanate-Llp dioxide and replacing potassium β- [fi- (benzyloxylcarbonyl) -D- -amirio-O - (p-hydroxyphenyl) acetamidojpenicillanate with triethylammonium-G- [N- (1-N, N-dimethylaminocarbonylpropen-E-yl) -D - <> (-amino-IX - phenylacetamidojpenicillanate to give 1,1- dioxo-60 (-chloro-penicillanoyloxymethyl-6- [N- (1-N, N-dimethylaminocarbonylpropen-ê-yl) -D- (X-amino-d-phenylacetamido] penicillanate.

The protecting group in the above-obtained intermediate was removed by acid-catalyzed hydrolysis (pI-Lztåš) in a mixture of equal parts by volume of ethyl acetate and water. The resulting aqueous phase was separated and lyophilized to give the title compound as an amorphous product. Example 7. Bris-bromophenicillanoyloxymethyl-6- (D-OE-amino-N-phenylacetamido) penicillanate hydrochloride. I worked in the same manner as in Example 2 (A) but replaced the chloromethylpenicilanate-LI dioacid with chloromethyl-β-bromopenicillanate and replaced potassium β-LN- (benzyloxycarbonyl) -D- (K-amino- (α- The (p-hydroxyphenyl) acetamide phosphenicylanate with the triethylammonium-β- [N- (1-N, N-dimethylaminocarbonylpropen-α-yl) -D-β-amino- ° (-phenylacetamido] penicillanate to give 6,5-bromopenicillanoyloxymethyl -B- [N- (1N, N-dimethylaminocarbonylpropen-2-yl) -D- ° E -amino-O (-phenylacet-amido / penicillanate).

The protecting group of the intermediate obtained above was removed by acid-catalyzed hydrolysis (pH 3 ~ 3) in a mixture of equal volumes of ethyl acetate and water. The resulting aqueous phase was separated and lyophilized to give the title compound as an amorphous product. Example 8. 1,1-Dioxopenicillanoyloxymethyl-6- (D-N -amino-G-phenylacetamido) penicillanate hydrochloride.

(A) Tetrabutylammonium 6- (D-β-amino-M-phenylacetamido) penicillanate.

To a stirred, cooled (500) mixture of 8.08 g of 6- (DN -amino- & -phenylacetamido) penicillanic acid trihydrate and 6.9 g of tetrabutylammonium hydrogen sulfate in 20 ml of water and 10 ml of dichloromethane were slowly added 20 ml of an 2N aqueous solution of sodium hydroxide. The organic layer was separated, and the aqueous phase was extracted with 20 ml of dichloromethane.

The combined dichloromethane layers were dried over magnesium sulfate and evaporated in vacuo to a viscous oil. This oil was dissolved in 100 ml of ethyl acetate, and the residual dichloromethane was removed under reduced pressure. After allowing the solution to stand overnight at 5 ° C, the precipitated crystals were collected, after which they were washed with ethyl acetate and dried in vacuo. The title compound was obtained in the form of colorless, slightly hygroscopic crystals with a melting point of 125-13000 (decomposition).

(B) 1,1-dioxopenicillanoyloxymethyl-6- (Df-amino-N-phenylacetamido) penicillanate hydrochloride.

To a stirred suspension of 2.95 g of tetrabutylammonium 6- (D-d-amino-M -phenylacetamido) penicillanate in 20 ml of ethyl acetate and 5 ml of dichloromethane was added a solution of 1.9 g of iodomethyl-1,1-dioxopenicillanate in 10 ml of ethyl lactate. After a few minutes, an almost clear solution was obtained. Dichloromethane was removed under reduced pressure, and precipitated tetrabutylammonium iodide was filtered off. The title compound was transferred from the filtrate to an aqueous phase (25 ml) using a 1N aqueous solution of hydrogen chloride (pH 3.0, 5 ° C), after which the title compound was transferred from the aqueous phase back to an organic phase (25 ml of ethyl acetate) using a 0.5M aqueous solution of sodium bicarbonate (pH 7.0, SOC). The organic layer was washed with water, and the desired compound was again transferred to an aqueous phase as described above. To this aqueous phase was added n-butanol, and the water was removed by azeotropic distillation in vacuo. The title compound was obtained as colorless crystals with a melting point of 175-17700 (decomposition), Äïtfšo '+2010 (c = 1, H2O). 99.4 g H Example 9. 1,1-Dioxoipenicillanoyloxymethyl-6- (D-q-amino- (X-phenylacetamido) penicillanate.

To a cold (500) solution of 631 mg of the compound prepared in Example 8 in 10 ml of water was added 10 ml of ethyl acetate, after which the pH of the mixture was adjusted to 7.0 by adding a 0.5M aqueous solution of sodium hydrogencarbonate with stirring. . The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. This gave the title compound as a colorless solid. The IR spectrum (KBr) showed strong bands at 1780 and 1690 cm -1. Example 10. 1,1-Dioxopenicillanoyloxymethyl-6- [D-1-amino-N- (p-hydroxyphenyl) acetamide] phenicillanate hydrochloride.

(A) Tetrabutylammonium 6- [D-Ü-emino-Ü-Kp-hydroxyphenyl) acetamido] penicillanate.

To a stirred, cold (5 ° C) solution of 3.57 g (10.5 mmol) of tetrabutylammonium hydrogen sulfate in 10 ml of water was added 20 ml of a 9: 1 by volume mixture of dichloromethane and n-butanol. Then 2N sodium hydroxide solution was added to adjust the pH to about 3; Then 2 g (10 mmol) of 6- [D-W.-amino-N- (p-hydroxyphenyl) acetamide] penicillanic acid trihydrate (amoxicillin trihydrate) are added, and the pH is adjusted to 9 with 2N sodium hydroxide solution.

The organic layer was separated, and the aqueous phase was extracted twice with a mixture of dichloromethane and n-butanol in a volume ratio of 9: 1 (10 ml each time). The combined extracts were concentrated in vacuo to a viscous oil, and this residue was dissolved in 50 ml of ethyl acetate. Crystallization was induced by scraping, and after the mixture was allowed to stand at 500 for 2 hours, the crystals formed were filtered off, after which they were washed and dried. This gave the title compound with a melting point of 1U8-15100 (decomposition).

(B) 1,1-dioxopenicillanoyloxymethyl-β-β-N- "amino-fl- (p-hydroxyphenyl) acetamide] penicillanate hydrochloride.

To a stirred, cooled (5 ° C) solution of 606 mg (1 mmol) of tetrabutylammonium 6- [D-1% -amino-N- (p-hydroxyphenyl) acetamido] penicillanate in 5 ml of acetonitrile was added a solution of 573 mg (1 mmol) of iodomethyl 1,1-dioxopenicillanate in 2 ml of acetonitrile (After stirring for 10 minutes at 500, 50 ml of ethyl acetate were added, after which the solvent was evaporated in vacuo. The residue was dissolved in 20 ml of ethyl acetate, and crystallized tetrabutylammonium iodide by filtration.

To the filtrate was added 10 ml of water, and the pH was adjusted to 3 zl 8001099-4 with N hydrochloric acid. The aqueous phase was separated and lyophilized to give the title compound as a colorless powder. The NMR spectrum of (CD 3) 2 SO showed signals at δ = 1.37 (S, on; 2-cgs), 1.5o (S. GH; 2- C53), 3.u6 (m, za, 6a-3 and 6ß-5), u.46 (S, in; 3-3), u.57 (S, 1H; 3-E), 5.oh ( ss, 1n; cgnaz), 5.27 (m, ln; 5-g), 5.58 (m, za; 5-3 and 6-g), 5.96 (bs, 2H, ocg, o), 6.87 and 7.37 (za, J = 8.5nz, hu; arom. Og) ppm.

TMS was used as internal reference.

Example 11. -1- (1,1-dioxopenicillanoyloxy) ethyl 6- (D-W-amino-Q-phenylacetamido) penicillanate hydrochloride. To a solution of 5.9 g (10 mmol) of tetrabutylammonium 6- (DM - amino-1% -phenylacetamido) penicillanate in 10 ml of dichloromethane and 10 ml of ethyl acetate was added a solution of 10.55 U of 1-iodoethyl- 1,1-dioxopenicillanate with a purity of H0% (corresponding to U, 22 g of pure product; 10.9 mmol) in 30 ml of ethyl acetate. The clear solution was immediately inoculated with tetrabutylammonium iodide, after which dichloromethane was removed in vacuo.

Precipitated tetrabutylammonium iodide was filtered off. From the filtrate the title compound was transferred to an aqueous phase (50 ml) using N hydrochloric acid (pH 3.0, 500), and from this aqueous phase the title compound was transferred to an organic phase (50 ml of ethyl acetate) using sodium bicarbonate (pH 7.0, 500). The organic phase was washed with water, and the title compound was again transferred to an aqueous phase as described above. After lyophilization of the aqueous phase, the title compound was obtained as a colorless powder.

The NMR spectrum (D20) showed signals at δ = 1.38 S, 6n; 2; cg¿), 1.u3 (S, ßu; 2-C33), 1.55 (S, 3H; 2-cg3), 1.56 (a, 3H; cncgj), 3.50 (m, an; óa-g and 6ß -5), u.53 (s. 1H; ß-a), h-ss and 1159125, 1H; 3-11), h-vß (m. W; 5-g), 5.26 (S, 1n; cgnnz), 5.51 (S, en; 5_n Om] 6-Q), 56.95 (m, 1n; cgcu3), and 7.51 (5, 5n; arom. og) ppm. Example 12. 6β-Bromopenicillanoyloxymethyl-6- (D-O-amino-N-phenylacetamido) penicillanate hydrochloride.

To a stirred solution of 0.82 g (1.0 mmol) of tetrabutylammonium I 6- (DG -amino-N -phenylacetamido) penicillanate in a mixture of 2.8 ml of ethyl acetate and 1.0 ml of dichloromethane was added a solution of 0 60 g (1.0 mmol) of iodomethyl β-bromopenicillanate in 5.6 ml of ethyl acetate. After stirring at room temperature for a few minutes, crystalline tetrabutylammonium iodide began to precipitate. The dichloromethane was removed from the reaction mixture under reduced pressure, and the crystals were filtered off and washed with ethyl acetate (2 x 2.5 ml). The filtrate was washed with 5 ml of water, to the organic phase was added 10 ml of fresh water, and the pH of the aqueous phase was adjusted to 3.1 by adding 1N hydrochloric acid with stirring. The aqueous phase was separated and freeze-dried to give the desired compound as a colorless foam. The NMR spectrum (D 2 O) showed signals at (f = 1.311 (s, 3H; z-cgß), 1.36 (s, 3H; 2) -cg3), 1.1s3 (s, 311; rl-cgqß 1.58 (s, 311; z-cgß), 14.51. (s, in; 3-5), 11.75 (S. 111; 3-3). 5.211 ( s, in; cgnnq), 5.I46-5.62 (m, un; 5-3; oc »6-11), 5.81 * (bs, ZH; OCQBO), and 7, h7 (s, SH; arom. C ) ppm.

Example 13. 1,1-Dioxo-6 ° (-chloropenicylanoyloxymethyl-G- (D-O (-amino-d-phenylacetamido) penicillanate hydrochloride.) By working in the same manner as in Example 12 but replacing iodomethyl-β The bromophenicylanate with iodomethyl 1,1-dioxo-60 (-chloropenicillanate was obtained the desired compound as a colorless foam.

The N1V1R spectrum (D20) showed signals at d '= 1.35 (s, 6H, 2415,). 1,111 (pp. 2-03). 1.ss "(s. An; 2-033). 11.57 (sm 3-5). 11.13 (s. M; ag). 5-08 (sm s-gsllsfé-ë). 5.26 (s, m, Omnia ). 5,311 (p. 1Hrs-I¿ @ 11 @ f6-'1¿) ~. 5.119 (p. 211; sg and 6-11). 5.91; (b, 2H; 0C§20); and 7.119 (p. , SH; arom. Cg) ppm.

Example 111. 1,1-Dioxopenicillanoyloxymethyl-α- (D-O (-amino- (X-phenylacetamido) penicillanate hydrochloride. I (A) 1,1-dioxo-6 (X-bromopenicillanoyloxymethyl-6- (D- X - amino-Å - phenylacetamido) penicillanate hydrochloride - By working in the same manner as in Example 12 but replacing the iodomethyl G / S bromopenicillanate with iodomethyl 1,1-dioxo-60 (bromobenicillanate, it was obtained desired compound as a colorless foam.

The NMR spectrum (D 2 O) showed signals at d 51.36 (s, 6H; 1.141 (s, an; 2-cg3), 1.511 (s, 3n; z-cga), 4.57 (s, m; 2'C.g3) ö 3-31) - 11-71 (S. IH. 3-11). 5-09 (S. IH; 54§ <> 1. 6-5), 5.27 (s, in, fl ëN fl g). s-as (p. 111: 5-11 el-GI-ä). 5.50 (p. 211; 5-5 and ó-g). 5.9 '(b, 211; ocgao), and 7.5o (s, _51x; arom. Cg) ppm. (B) 1,1-Dioxopenicillanoyloxymethyl-6- (D-pho-amino-N-phenyl-acetamido) penicillanate hydrochloride.

To a solution of 1,1-dioxo-65-bromopenicillanoyloxymethyl 6- (D-'fk-amino-fa-phenylacetamido) penicillanate (liberated from 1.36 g of the corresponding hydrochloride) in 50 ml of ethyl acetate was added 25 ml of water and 0.7 g of a catalyst consisting of 10% palladium on carbon.

The resulting mixture was shaken in a hydrogen atmosphere for 110 minutes. After removal of the catalyst by filtration, the pH of the aqueous phase is adjusted to 2.5 with 1N hydrochloric acid. From the separated aqueous phase, the title compound was transferred to an organic phase (25 ml of ethyl acetate) using an aqueous solution of potassium bicarbonate (pH 7.0, 5 ° C), after which the title compound was transferred to a fresh aqueous phase using 1N hydrochloric acid (pH 2). , 7). After lyophilization of the aqueous phase, the title compound was obtained as a colorless powder.

The NMR spectrum of the product was identical to the spectrum of the compound described in Example 1.

Example 15 β-Iodo-penicillanoyloxymethyl-6- (D-β-amino-N-phenylacetamido) penicillanate hydrochloride.

The procedure was the same as in Example 12, but the iodomethyl-6β-bromopenicillanate was replaced with iodomethyl-6β-iodine penicillanate. The above title compound was obtained as a colorless foam.

The NMR spectrum (D 2 O) showed signals at δ = 1.35 (S, 3n; 2-cg3), 1.38 (S. BH; 2-Cë3). 1-ha (S. 3H; .2-C53). 1.60 (s, ara-scan, 11.56 (s. M; aa). Mh (s. 1H: 3-21) - 5-22 (S, in; C§NH2). 5.3-5.7 (m. 4H; 5 -H 2 -H 6 -H). 5.92 (bs, 2H; Qczo), and 7.h9 (s, 5H; arom. Cg) ppm.

Example 16. 6β-Chloropenicillanoyloxymethyl- 6- (D-I-amino- '' - phenylacetamido) penicillanate hydrochloride.

By working in the same manner as in Example 12 but replacing the iodomethyl-β-bromopenicillanate with iodomethyl-β-chloropenicillanate, the title compound was obtained as a colorless foam.

The IR spectrum (KBr) showed strong bands at 1790-1770 and 1690 cm -1. Example 17. Clavulanoyloxymethyl-6- (D-d-amino-N-phenylacetamido) penicillanate hydrochloride.

(A) Iodomethyl-β- (D- * X-azido-Oβ -phenylaoethamide-penicillant.

To a solution of 1.32 g (3 mmol) of chloromethyl 6- (D-N -azido-K-phenylacetamido) penicillanate in 25 ml of acetone was added 1.80 g (12 mmol) of sodium iodide. The resulting mixture was stirred at room temperature for 18 hours. The precipitate formed was then filtered off, and the filtrate was evaporated in vacuo. The residue was extracted with 25 ml of ethyl acetate, after which the extract was concentrated to a volume of cag ml. The resulting concentrate was subjected to column chromatography on silica gel, eluting with a mixture of equal volumes of hexane and ethyl acetate. The fractions containing the desired compound were combined and evaporated in vacuo to give the title compound as a yellowish oil.

The NMR spectrum (CDCl 3) showed signals at d = 1.58 (S, 3n; 2-cgß). 1.67 (s. 5.13 (s. W: Gay). s-sz-s-ßé (m. 211; s-g and e-g). 6.00 (me, za; 0C§2J) | 7-4 (8.5H; arom. Cg) and 7.0-7.U (m, 1H; QONQ) ppm.

TMS was used as an internal reference.

(B) Clavulanoyloxymethyl-G- (D- (1-azido-IX -phenylacetamido) -penicillanate. To a solution of 578 mg (0.73 mmol) of iodomethyl-6- (DX -azido-d -phenylacetamido) penicillanate To 3.8 ml of hexamethylphosphoric acid triamide was added 90 mg (0.1 HH mmol) of lithium clavulanate, after which the resulting mixture was stirred at room temperature for 1 hour, the mixture was then diluted with 90 ml of ethyl acetate and washed with water (3 x 20 ml) and then with a saturated aqueous solution of sodium chloride (10 ml), after which it was dried and evaporated in vacuo.

The yellow oil thus obtained was purified by column chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate in the volume ratio lzü. The desired compound was obtained as a pale yellow foam.

The NMR spectrum (CDCl 3) showed signals at tf = 1.51 (S, 3H; z-cgj), 1.6u (S, 3H; 2-C33), 3.11 (a, J = 17 az, 1H; 6-3) . 3.51 (ad, J1 = 17 Hz, J2 = 3 Hz, 1H; 6-5), h.25 (d, J = 7 Hz. An; cg2oH); h.51 (S, 1H; 3-5), 4.92 (m, 1H; = cg-), 5.13 (s, 1n; 5-5), 5.13 (5, 1H; 3-g), 5.5- 5.8 (m, 3u; 5-g, 6-g, and own), 5.89 (A fl n fl an; ocgzo), 7.16 (d, J = s.5 Hz, 1H¿ Cong), and 7.h1 (m, SH ; arom. CE) ppm. TMS was used as an internal standard.

(C) Klavulanoyloxymethyl-β- (D- ((amino-O) -phenylacetamideM-enicillanate hydrochloride).

A solution of 130 mg (0.22 mmol) of clavulanoyloxymethyl-6- (DK-azido-Ü-phenylacetamido) penicillanate in 20 ml of ethyl acetate was introduced into a three-necked flask equipped with a tube for inflow and outflow. of gas, in a glass-calomel combination electrode and a burette. 20 ml of water and 150 mg of a catalyst consisting of 10% palladium on carbon were added. The system was purged with nitrogen gas. Hydrogen was then passed through the stirred reaction mixture, and the pH was maintained at 2.5 by the simultaneous addition of 0.1N aqueous hydrogen chloride. When the consumption of acid ceased, the flask was purged with nitrogen and the catalyst was filtered off. The aqueous layer was separated, filtered and lyophilized to give the desired compound as a colorless powder.

NMR spectrum 1YCD3) 3SQ] showed signals at δ = 1.30 (s, 3n; α-cgß), 1.141; (s, 3n; z-cgß), 3.12_ (d, J = 17 Hz, ln; 6-5), 3.65 (de, J1 = 17 Hz, J2 = 3 nz, in; 6-5), 14.00 (m, zn; eggs), 15112 (s, in; 3-31), 11.75 (m, in; -Cä =). 5.15 (bs. 1H; 3-5), 5.11o-5.75 (m, 3n; 5-3, δ-g-wçh cgnnz), 5.85 (Anw, 2n; ocgzo), 7.50 (m, 5n; arom. And ), and 9.115 (d, J = 7 nz, in; CONE) pbm_ TMS was used as internal reference. Example 18. Clavulanoyloxymethyl-β- [D-N -amino-d- (p-hydroxyphenyl) acetamide] penicillanate hydrochloride. 1 (A) Chloromethyl-δ-ZN-benzyloxycarbonyl-D- (X-amino-Oš - (- hydroxyphenyl) acetamideQ] penicillanate.

To a suspension of 2.5 H6 (5 mmol) of potassium 6- [N-benzyloxycarbonyl-1-D-vk-amino- * X- (p-hydroxyphenyl) acetamide] penicillanate in 25 ml of N, N-dimethylformamide was added 2 , 18 ml (30 mmol) of chloroiodomethane, whereupon the resulting mixture was stirred at room temperature for 3 hours. After dilution with 100 ml of ethyl acetate, the mixture was washed with water (U x 25 ml), then dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of equal volumes of ethyl acetate and hexane.

There was thus obtained the desired compound as a yellowish oil.

(B) Clavanoanoyloxymethyl-6- [D- [(amino) C (- (p-hydroxyphenyl) -acetamidolpenicillanate hydrochloride.

The procedure was the same as in Examples 17 (A), 17 (B) and 17 (C) but replaced the chloromethyl 6- (DM-azido-IX-phenylacetamido) penicillanate with chloromethyl- 6- [N-benzyloxycarbonyl-Do ( -amino-M-% (p-hydroxyphenyl) -acetamide grouppenicillanate. After lyophilization, the title compound was obtained as a colorless powder.

The IR spectrum (KBr) showed strong bands at 1775 and 1690 cm -1. Example 19. 1,1-Dioxopenicillanoyloxymethyl-6- (D, lf4 (-carboxy-M '-phenylacetamido) penicillanate sodium salt.

(A) 1,1-dioxopenicillanoyloxymethyl-6- (D, L-O {-benzyloxycarbonyl-d-phenylacetamido) penicillanate.

To a suspension of 0.98 g (2 mmol) of sodium 6- (D, LQ -benzyloxycarbonyl-M-phenylacetamido) penicillanate in 10 ml of N, N-dimethylformamide was added 0.75 g (2 mmol) of iodomethylpenicillanate -1,1-dioxide. The resulting mixture was stirred at room temperature for 30 minutes. Then 50 ml of ethyl acetate were added, and the mixture was extracted with a saturated aqueous solution of calcium chloride (5 x 12 ml), dried and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel, eluting with a mixture of equal volumes of hexane and ethyl acetate. There was thus obtained the desired compound as a yellowish oil.

The NMR spectrum, (CDCl 3) showed signals at d '= 1.Ä-1.6 (m, un; 24:53), 3.h6 (m, an; 6-3), (AA-ins (m, an ; 3-5 and 'cgco), u.56-L ».65 (m, an; g-goch. Sg), 5.19 (s, an; Pncgzo), _ 5_u-5.75 (m, an; 5.3 and mg ), 5.9 (Askv, an; ocggo), 7.3 (S, 5H; aroma C fl), 7.j5 (S, SH; aroma. C fi), and 7.5-7.95 (mv 135 CON§) ppm. TMS was used as internal Reference 7 (B) -1,1-Dioxopenicylanovloxymethyl-6- (D, L-α-carboxy-d-phenylacetamido) penicillanate sodium salt.

To a solution of 1.0 g (1.1 μm) of 1,1-dioxopenicillanoyloxymethyl-6- (D, LM-benzyloxycarbonyl-Q-phenylacetamido) penicillanate in 25 ml of ethyl acetate was added 25 ml of water and 1.0 g of a catalyst consisting of 10% palladium on carbon. The pH of the resulting mixture was adjusted to 7.0. Hydrogen was bubbled through the stirred reaction mixture, and the pH was maintained at 7.0 by adding a 0.1N aqueous solution of sodium hydroxide. When the consumption of base ceased (after about 1 hour), the catalyst was filtered off, and the aqueous phase was separated, filtered and lyophilized. The desired compound was obtained as a colorless powder. The NMR spectrum '(D20) showed signals at d' = 1, H7 (s, 31:; a-cga), 1.53 (s, BH; 2-C fi3 h 1-63 (s, GH; 2-C fl3). (m, zu; 6-33; ß.12 (s. m: 3-11). mn (=. w: 2-5.). 0.70 (a, m; cgco), 5.00 (m, 1HZ S- δ). 5-14-5-7 (m. 2Hi 5..¿1__ocn ó-g), anno (ss, 2H; 002320), 7.112 (s. SH; arw-CH) ppm, TMS was used as external reference Example 20. 1,1-Dioxopenicillanoyloxymethyl-Gß -aminopenicillanate hydrochloride.

(A) Tetrabutylammonium-Qβ -aminopenicillanate.

To a stirred, ice-cold mixture of α, 32 g (20 mmol) of Ä-amino-penicillanic acid, 6.8 g (20 mmol) of tetrabutylammonium hydrogen sulfate, 50 ml of dichloromethane and 20 ml of water were slowly added a solution of 1.60 g (H ) sodium hydroxide in 3.5 ml of water. The organic layer was separated, and the aqueous layer was extracted with chloromethane (2 x 25 ml).

The combined organic layers were dried and evaporated in vacuo to give the desired compound as a viscous oil. The IR spectrum (CHCl5) showed strong bands at 1760 and 1610 cm-1. (B) 1,1-dioxopenicillanoyloxymethyl-6,5-aminopenicillanate hydrochloride.

To a solution of 5.1 g (11 mmol) of tetrabutylammonium-Qβ -aminopenicillanate in 25 ml of ethyl acetate was added a solution of 5.73 g (10 mmol) of iodomethylpenicillanate-1,1-dioxide in 25 ml of ethyl acetate. After stirring for 15 minutes at room temperature, the precipitate formed was filtered off, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on Sephadex æ, LH 20, eluting with a mixture of chloroform and hexane in a volume ratio of 65:35. The purified product was dissolved in 25 ml of ethyl acetate. To the resulting solution was added 25 ml of water, and the pH of the mixture was adjusted to 2.0 by adding 2N hydrochloric acid. The aqueous phase was separated and lyophilized to give the title compound as a colorless powder. .

The NMR spectrum (C20) showed signals at Cf = 1.52 (s, 3H; 2-cg3), 1.60 (s, 311; z-cga), 1.65 (s, an; 12453), 1.76 (s, 3H; z- cgß), 3.52-3.8 (s, an; 6-5), uns (s, in; 3-g), u.9o (s, in; 3-5), 5.o5-5.25 (m, m; 5-33), 5.20 (a, J = u Hz, m; ó-g), 5.78 (a, J = Linz, in; 5-2,), and 6.08 (bs, an; ocg, o) ppm_TMS was used as an external reference.

Example 21. 1,1-Dioxopenicillanoyloxymethyl-β- (D-1-amino-IX-phenylacetamido) penioillanate hydrochloride.

To a stirred suspension of 1.98 g (10 mmol) of D-O (-phenylglycyl chloride hydrochloride in 25 ml of dichloromethane was added at 0 ° C 1.68 g (20 mmol) of sodium bicarbonate, then 5.98 g (8 mmol) were added. mmol) 1,1-dioxopenicillanoyloxymethyl-6-aminopenicillanate hydrochloride.

After stirring vigorously at 000 for 1.5 hours, the reaction mixture was evaporated in vacuo. The residue was taken up in an ice-cold mixture of 25 ml of ethyl acetate and 25 ml of saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, 20 ml of water were added, and the pH of the mixture was adjusted to 2.5 by adding 2N hydrochloric acid. The aqueous phase was separated and lyophilized to give an amorphous powder which crystallized from a mixture of ethanol and butan-2-one. This gave a product identical to the product described in Example 8.

Example 22. 1,1-Dioxopenicillanoyloxymethyl- 6- (D-β-emino-d-phenylacetamido) penicillanate hydrochloride.

(A) Potassium 6- [Û- (1-dimethylaminocarbonylpropen-2-yl) -D-CW-amino-d-phenylacetamide] penicillanate.

To a solution of 27.3 g (88 mmol) of triethylammonium-6- [N- (1-dimethylaminocarbonylpropen-2-yl) -D-O] -amino-N -phenylacetamide quenicillanate in 1 liter of acetone was added dropwise H9 ml of a 1M solution of potassium 2-ethylhexanoate in acetone. After stirring at room temperature for 2 hours, the precipitate formed was filtered off. The precipitate was recrystallized from a mixture of methanol and isopropanol to give the title compound, m.p. 201-203 ° C (dec.). [OIL] = + 17H ° (c = 1, water).

(B) 1,1-Dioxopenicillanoyloxymethyl-- (D- ° (-amino-Uš -phenyl-acetamido) penicillanate hydrochloride 3 To an ice-cold solution of 5.119 g (11 mmol) of potassium 6- [v- (1 -dimethylaminocarbonylpropen-2-yl) -O-O (-amino-d-phenylacetamide] penicillanate In 25 ml of N, N-dimethylformamide was added 3.73 g (10 mmol) of iodomethyl penicillanate-1,1-dioxide The resulting mixture was stirred at 500 for 30 minutes After dilution with 100 ml of ethyl acetate, the mixture was extracted with water (H x 25 ml) and then with a saturated aqueous solution of sodium chloride (25 ml). The organic phase was dried and evaporated. In vacuo to half the original volume, 25 ml of water were added to the concentrate, and the apparent pH of the mixture was adjusted to 2.5 by adding 2N hydrochloric acid with stirring. During the hydrolysis, this pH is established by adding additional hydrochloric acid. When the consumption of acid ceased (after about 30 minutes), the aqueous phase was separated and lyophilized to give a compound, v which after crystallization in a mixture of ethanol and butan-2-one was found to be identical to the compound described in Example 8. Example 23 1,1-dioxo-6H- (2,0-dimethoxybenzamido) penicillanoyloxymethyl-β- (D-O1-amino-d-phenylacetamido) penicillanate hydrochloride. 0.75 g (2 mmol) of sodium β- (D-OK-amirxo-O (-phenylacetamido) penicillanate was added to an ice-cooled solution of 1.11 g (2 mmol) of iodomethyl-1,1-dioxo- Sß .- (2,6-dimethoxybenzamido) penicillanate in 10 ml of dimethylformamide The resulting solution was kept in an ice bath for 30 minutes, after which it was diluted with 340 ml of ethyl acetate and washed with water (14 x 10 ml). was stirred with water while adding hydrochloric acid to pH 2.5 The aqueous phase was separated and lyophilized to give the title compound as a colorless powder. The NMR spectrum (CDBOD) showed signals at d = 1.117 (s, BH, 2-Cëš), 1.50 (s, ÖH; 2-CÉ3), 1.58 (s, BH, 2-Cëj), 3.83 (S, ÖH; 0C fi š), 11.50 (s, 1H; Bh), 14.69 (s, 1H ; sh), 5.18 (s, 1H; C§NH2), 5-21 (d, J = u Hz, 1H; 5-E), 5.u-5.8 (m, 2H; 5-g and 6-5 ), 6.00 (m, 2H; OCLIEO), 6.27 (d, J = ¿1 Hz, 1H; 6-11), 6.73 (d, 2H; arom. B- fi and 5-_I: I_), 7.113 (t , 1H; arom. Ä- fi), and 7.53 '(s, 5H, arom. CE) ppm.

TMS was used as internal reference.

Example 211. 1- (1,1-Dioxopenicilanoyloxy) ethyl-6-α) -α (amino-β-hydroxyphenyl) acetamide polynicillanate hydrochloride.

By working in the same manner as in Example 10 (B) but replacing the iodomethyl-1,1-dioxopenicillanate with 1-iodoethyl-1,1-dioxipenicillanate, the title compound was obtained as a colorless powder.

The IR spectrum (KBr) showed strong bands at 1785, 1690 and 1655 cm -1.

Example 25. 6fl-Bromopenicillanoyloxymethylo-δ- [D-O (-amino-IX- (p-hydroxyphenyl) acetamido] penicillanate hydrochloride.

By working "in the same manner as in Example 10 (B) but replacing the iodomethyl-1,1-dioxopenicylanate with iodomethyl-β-bromopenicillanate, the title compound was obtained as a pale yellow powder.

The IR spectrum (KBr) showed strong bands at 1790, 1775 and 1690 cm -1.

Example 26. fi-pen-β-penicillanoyloxymethyl-6- [D-Û-amino-amino-d- (p-hydroxyphenyl) acetamido] penicillanate hydrochloride.

By working in the same manner as in Example 10 (B) but replacing the iodomethyl-1,1-dioxopenicillanate with iodomethyl-fi-ion-β-elliplanate, the title compound was obtained as an amorphous powder.

The IR spectrum (KBr) showed strong bands at 1790, 1775 and 1685 cm *. '

Claims (8)

f i nso0 ~ 1o99-4 38 P a t e n t k r a v 1. Chemical compound, which has the general formula R -CH-CÛ-NH I; i S \ _ l | Å- _ Wherein R 1 represents a phenyl group, an Afhydroxyphenyl group, a 1,4-cyclohexadienyl group or a 3-thienyl group wherein R 2 represents a primary amino group or a carboxy group, wherein R 6 represents a hydrogen atom, a lower alkyl group, a phenyl group or a benzyl group And where A represents either (a) a group of the formula _ l O nu = 10 R gh - 7 5 \ 2_ s / _ (II) -fa ._41 ° á H x fi- o- 1 wherein R 4 represents a hydrogen atom or a halogen atom, and R 5 represents a hydrogen atom or an amino group, at least one of the symbols R 4 and R 5 representing hydrogen; or (b) a group of the formula Smoke (III) / O / wherein R 6 represents a halogen atom; or (c) a group of the formula 'in 8801099-4 39 (IV) / r-N. H 3-0- wherein R7 represents a hydroxy group, and salts of the compound of formula I with pharmaceutically acceptable, non-toxic acids or bases. The pure diastereomers of the compound of formula I according to claim 1, mixtures thereof and salts of the diastereomers and mixtures thereof. = "' A compound according to claim 1, characterized in that R 2 represents a primary amino group and that R 1 and A have the meanings given in claim 1; and salts of the compound of formula I with pharmaceutically acceptable, non-toxic acids. 4. A compound according to claim 1, characterized in that R 2 represents a carboxy group and that R 1 and A have the meanings given in claim 1; and salts of the compound of formula I with pharmaceutically acceptable, non-toxic bases. d A process for the preparation of a compound of formula I according to claim 1, characterized in that (a) a compound of formula '[Ulla UI I: I R -cu-co-NH 1 | K B o______N (V); § H EO-? HA O. R3 where R1, R3 and A have the meanings given in claim 1, and B represents an azido group, a protected amino group or a protected carboxy group, are subjected to catalytic hydrogenolysis or hydrolysis depending on the meaning of the symbols A and B; or that (b) a 6-aminonenicillanic acid ester of the formula ¿soo1o99-4 „zNÉ ~ ï / S \ F '.i. (xx) or a trialkylsilyl derivative thereof, wherein R 3 and A have the meanings given in claim 1, are reacted with a reactive derivative of an acid of the formula '-R 1 -H-CQQH. I (XII) 'B where n *, Kal-I; or that (c) an aminopenicillin of formula 1 has the meaning given in claim 1 and B represents NH3 u H nl-fu-cp-nu E ys \ ä (xml) m2 'I "o = N -7' 11 * YoM Where R 1 has the meaning given in claim 1 and M represents a cation, reacted with a compound of the formula A-TH-X I (VIII) R 3 where 33 and A have the meanings given in claim 1 and X represents a halogen atom or a similar leaving group, after which the compound of formula I formed is recovered either as such or in the form of a salt thereof. Process according to Claim 5, alternative (c), characterized in that the symbol X in formula VIII represents an iodine atom. ”* If soo1o99-4 Pharmaceutical composition for the enteral, parenteral or topical treatment of patients (including animals) suffering from infectious diseases, characterized in that it contains as active ingredient a compound of formula I according to claim 1 together with a non-toxic, pharmaceutically acceptable carrier . Pharmaceutical composition according to claim 7, characterized in that it contains the active ingredient in combination with a known amidinopenicillanic acid derivative, the ratio of the active compounds being between 1:20 and 20: 1, preferably between 1 : 5 and 5: 1.